PROJECT SUMMARY/ABSTRACT Telomere length (TL) plays a central role in maintaining cellular proliferative potential and genome stability, leading many investigators to hypothesize that telomere shortening over the life course is a critical mechanism underlying many age-related health conditions. In epidemiological and clinical studies, individuals with relatively short telomeres in peripheral blood cells are often observed to be at increased risk for a wide array of diseases, including cardiovascular conditions, dementia, and multiple types of cancer. However, these associations are difficult to interpret, in part because it is not clear how well TL in peripheral blood cells reflects TL in the tissues most relevant to disease; no studies have addressed this issue in a comprehensive fashion. Furthermore, it is unclear if tissue-specific TL actually reflects levels of genomic instability and DNA damage measured in the same tissue. In this proposal, our first aim is to address this knowledge gap by assessing the correlation between TL measured in whole blood and TL measured in various cancer-prone tissues (breast, colon, esophagus, kidney, lung, ovary, pancreas, prostate, skin, stomach, testis, and vagina) obtained from individuals who have donated tissues to the Genotype-Tissue Expression (GTEx) project. Approximately 100 individuals will be used for each comparison. We will generate data on average TL using a high-throughput, probe-based method that has superior performance compared to traditional PCR-based methods. Our second aim is to determine if tissue-specific TL is an indicator for chromosomal instability. To achieve this aim, we will generate data on somatic copy number variation (CNV) and copy-neutral loss of heterozygosity (LOH) events for each tissue type and assess the association between tissue-specific TL and abundance of somatic CNV and LOH events in the same tissue, using approximately 100 individuals for each analysis. CNV and LOH data will be generated using both probe intensity data and allele frequency data derived from high-density SNP arrays that will be run for DNA samples from each tissue. Finally, using existing data on single nucleotide polymorphisms (SNPs) at telomere maintenance gene loci known to effect leukocyte TL and/or cancer risk, we will search for evidence that these variants influence TL in a tissue-specific fashion. Addressing these knowledge gaps regarding correlations among tissue-specific TLs, the relationship between TL and chromosomal instability, and tissue-specific genetic effects on TL is a critical step towards elucidating the role of TL in the etiology of cancer and other common diseases. Our results will provide a foundation for the interpretation of findings from epidemiological studies of leukocyte TL and help guide the design of future studies aimed at elucidating the biological mechanisms and causal pathways linking telomere length and disease, with the long-term goal of using this knowledge to improving health and prevent disease.